The objective of the proposed research is to elucidate the role of GTPase in regulating the activities of adenylate and guanylate cyclase and of the microtubule polymerization system of human brain. GTP has been shown to be the substrate for guanylate cyclase, to be required for microtubule polymerization, and to modulate the stimulation of adenylate cyclase by dopamine. In order to understand the way in which cellular GTP pools function in the regulation of these interrelating systems, I intend to investigate the largely unstudied GTPase enzymes which compete with these other systems for GTP. Altered microtubule structure has been proposed as a characteristic neuropathology of patients with Alzheimer's disease, senile dementia and trisomy 21. Also, it has been proposed that an altered sensitivity of adenylate cyclase to dopamine may be involved in schizophrenia. Since the normal polymerization of microtubules and the normal stimulation of adenylate cyclase by dopamine are modulated by GTP, the activity of GTPase will influence both of these processes. A study will be undertaken to compare the properties of GTPase and of the related GTP -dependent systems (guanylate cyclase, adenylate cyclase, and microtubule polymerization) in brains from normals as opposed to brains from persons with Alzheimer's disease, trisomy 21, or schizophrenia. Of particular interest will be the requirement for GTP (Km or Ka) of these various systems since they must compete with each other. This investigation may provide insight into the biochemical etiologies of these diseases.